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International audience; Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I(2) = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed. ispartof: SEMINARS IN ARTHRITIS AND RHEUMATISM vol:55 ispartof: location:United States status: published

ImportanceThere is concern that post-acute SARS-CoV-2 infection health outcomes (“post-COVID syndrome”) in children could be a serious problem but at the same time there is concern about the validity of reported associations between infection and long-term outcomes.ObjectiveTo systematically assess the validity of reported post-acute SARS-CoV-2 infection health outcomes in children.Evidence ReviewA search on PubMed and Web of Science was conducted to identify studies published up to January 22, 2022, that reported on post-acute SARS-CoV-2 infection health outcomes in children (Findings21 studies including 81,896 children reported up to 97 symptoms with follow-up periods of 2-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16,986) and 2% to 53.3% in children without SARS-CoV-2 infection (n=64,910). Only 2 studies made a clear causal interpretation of an association of SARS-CoV-2 infection and the main outcome of “post-COVID syndrome” and provided recommendations regarding prevention measures. Two studies mentioned potential limitations in the conclusion of the main text but none of the 21 studies mentioned any limitations in the abstract nor made a clear statement for cautious interpretation. The validity of all 21 studies was seriously limited due to an overall critical risk of bias (critical risk for confounding bias [n=21]; serious or critical risk for selection bias [n=19]; serious risk for misclassification bias [n=3], for bias due to missing data [n=14] and for outcome measurement [n=12]; and critical risk for selective reporting bias [n=16]).Conclusions and RelevanceThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on post-acute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.KEY POINTSQuestionHow valid are the reported results on health outcomes in children after acute SARS-CoV-2 infection?FindingsWe identified 21 studies with only 6 using a controlled design. Reported post-acute health-outcomes were numerous and heterogeneous. The reported proportion of children with post-COVID syndrome was up to 66.5% in children with and 53.3% in children without SARS-CoV-2 infection. All studies had seriously limited validity due to critical and serious risk of bias in multiple domains.MeaningThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited and methodological robust evidence is urgently needed.

ObjectivesComprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist.DesignRepeated cross sectional study.SettingSwiss, German and Canadian research ethics committees (RECs).ParticipantsRCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292).Primary and secondary outcome measuresThe primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reportedResultsThe median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%–79%) in 2012 to 77% (IQR, 68%–82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%–72%) in 2012 to 76% (IQR, 64%–83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%–80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship.ConclusionsIn 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve.